Background: Patients with Fontan circulation are known to have increased systemic vascular resistance (SVR) however the underlying mechanisms are uncertain. We therefore further investigated the haemodynamic and vascular profile of Fontan patients. Methods: Eighteen adult subjects aged 25 ± 1 years who had undergone the Fontan procedure in their childhood (at age 6 ± 1 years) and not in clinical failure at the time of study were assessed for: 1) autonomic function, including direct muscle sympathetic nerve activity (MSNA) recording and sympathetic and cardiac baroreflex function, 2) endothelial function by means of reactive hyperaemia using the Endopat peripheral arterial tonometry (PAT) technique and plasma endothelin concentration and gene expression, 3) pulse wave reflections (digital and central augmentation index (AI)) and 4) haemodynamic changes to head-up tilt. Data were compared to that obtained in a group of 23 age- and weight-matched healthy subjects. Results: Fontan participants presented with elevated MSNA compared with controls (40 ± 5 vs 27 ± 3 bursts per 100 heartbeats), decreased cardiac baroreflex function (16.0 ± 3.3 versus 30.9 ± 3.7 ms·mm Hg- 1), normal sympathetic baroreflex function, decreased endothelial function (PAT ratio = 0.35 ± 0.09 vs 0.77 ± 0.11), and increased digital (5.9 ± 3.0% vs - 9.7 ± 2.3%) and central (1.4 ± 2.7% vs - 10.2 ± 3.9%) AI. Ten minute head-up tilt (60) induced greater reductions in cardiac output (CO) and stroke volume (SV) in Fontan patients (CO: - 28% vs - 11%, SV: - 40% vs - 25%). Conclusion: Adult Fontan patients have increased MSNA and altered endothelial function that are likely to contribute to their known increased SVR. Therapies aiming at reducing the peripheral resistances should target endothelial function and sympathetic activity.